Amyotrophic lateral sclerosis coexisting with primary sjögren’s syndrome: a clinical case series and exploratory transcriptomic analysis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration, while primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease with prominent immune dysregulation. Although immune-related alterations have been implicated in ALS and autoimmune diseases, the clinical coexistence of ALS and pSS remains poorly characterized. We aimed to describe the clinical features of patients with concomitant ALS and pSS and to explore peripheral blood transcriptomic patterns in independent ALS and pSS cohorts. We retrospectively identified patients with both ALS and pSS through systematic electronic health record screening and multidisciplinary clinical review. Clinical characteristics, disease chronology, treatment exposure, and outcomes were summarized. In parallel, we performed an exploratory transcriptomic analysis using publicly available peripheral blood datasets from independent ALS and pSS cohorts. Differentially expressed genes and overlapping inflammatory signatures were evaluated, with additional sensitivity assessment performed using an independent ALS cohort. Seven patients fulfilling diagnostic criteria for both ALS and pSS were identified. The temporal relationship between the two diseases was heterogeneous, with variable disease onset sequences and clinical trajectories. Immunomodulatory treatments were associated with transient improvement in systemic autoimmune manifestations in some patients, but no conclusions regarding modification of ALS progression could be established. Transcriptomic analyses identified overlapping upregulated genes between ALS and pSS cohorts, enriched in interferon- and NF-κB-related inflammatory signatures. However, these signatures represent commonly observed inflammatory responses across multiple disease contexts and should not be interpreted as evidence of ALS–pSS-specific biological convergence. Sensitivity assessment using an independent ALS cohort demonstrated partial reproducibility of selected non-specific inflammatory signatures across datasets. Taken together, these findings present two independent, exploratory observations: a rare clinical co-occurrence and a non-specific systemic inflammatory signature identified in unrelated public datasets, both requiring sensitivity assessment and serving as hypothesis-generating baselines for future studies.